Psychotic spectrum disorders (PSD) are difficult to differentially diagnose and treat, typically leaving their victims with lifetime disability. It is increasingly becoming recognized that traditionally distinct disorders such as schizophrenia, schizoaffective disorder and bipolar disorder with psychotic features share overlapping symptoms. For example, in addition to positive symptoms, PSD patients also experience deficits in cognitive control/executive functioning, which likely result from dysregulation of the mesocortical and mesostriatal pathways. Importantly, cognitive deficits contribute to deficits in interpersonal and occupational functioning, more traditional clinical symptoms (e.g., disorganized thinking) and are currently refractory to treatment. The current application will use novel recruiting strategies and novel multivariate analytic techniques to establish empirical, neuronally-based cluster metrics (i.e., circuit-level pathologies) that are associated with impairments in cognitive control (primary outcome) and everyday functioning (secondary outcome) in PSD regardless of traditional diagnoses (DSM-V). Other potential mediating variables evaluated in the current model include negative symptoms and disorganized thinking. We investigate potential causal mechanisms for these circuit- level pathologies by examining the aggregation of specific genetic mutations (single nucleotide polymorphisms; SNPs) within three neurotransmitter (dopamine, glutamate and GABA) signaling pathways, axonal guidance pathway, and synaptic long-term potentiation pathways based on our preliminary data. Finally, an exploratory aim evaluates whether the expression of cognitive control deficits across multiple psychiatric illnesses is mediated by each individual's total number of rare deletions in DNA (copy number variations; CNVs). To evaluate these hypotheses, 175 continuously recruited PSD patients will complete an extensive clinical battery and undergo multimodal neuroimaging. Evoked and intrinsic hemodynamic activity will be used in conjunction with white matter assays (diffusion tensor imaging) to investigate the integrity and connectivity of the cognitive control circuit (dorsal medial prefrontal cortex, lateral prefrontal cortex and caudate nucleus) during a multisensory cognitive control task with real-world validity. PSD patients will be classified into meaningful entities based on univariate and multivariate indices of grey/white matter pathology in the cognitive control network using a K-means algorithm. We will then determine the predictive validity of these clusters for describing deficits in cognitive control and everyday functioning, using the leave-one-out methodology to verify the model. Thus, the current application utilizes multiple units of analyses (genes, circuits, self-report, behavior, and paradigms) from the NIMH Research Domain Criteria to develop a novel classification system based on neurophysiological and genetic biomarkers of impaired cognitive control that spans traditional diagnostic categories. We are confident that moving beyond traditional nosologies will result in more meaningful diagnoses and ultimately more successful treatments for refractory symptoms, leading to substantial improvements in mental health care.